Multicomponent Synthesis of Isoindolinones by RhIII Relay Catalysis

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Multicomponent Synthesis of Isoindolinones by RhIII Relay Catalysis: Synthesis of Pagoclone and Pazinaclone from Benzaldehyde Yan Zhang,* Haiqian Zhu, Yuting Huang, Qi Hu, Yu He, Yihang Wen, and Gangguo Zhu* Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Zhejiang Normal University, 688 Yingbin Road, Jinhua 321004, China

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S Supporting Information *

ABSTRACT: A practical one-pot isoindolinone synthesis enabled by RhIII catalysis was developed. The advantage of this protocol is that it does not require pre-preparation of amide substrates, because RhIII participates in two reactions independently. This mild, operationally multicomponent process transforms a wide variety of commercially available aldehydes into the corresponding γ-lactams in good yields, thereby demonstrating that N-pyridin-2-yl benzamide is an effective directing group. Notably, the anxiolytic drugs pagoclone and pazinaclone can be directly prepared by this methodology.

N

powerful support to the design and synthesis of various skeletons such as lactams,5 pyridines,6 and others.7 In particular, rhodiumcatalyzed C−H olefination of benzamide with terminal olefins followed by annulation to form γ-lactam is one of the most classic of such syntheses (Scheme 1A). Li8 first reported RhIII-

itrogen-containing organic compounds are ubiquitous in nature and are essential to life. They are also important intermediates and products of the chemical and pharmaceutical industries. Among these, isoindolinones represent a significant class of heterocycles that are widely found in natural products and biologically active compounds.1 Some representative examples of these compounds are depicted in Figure 1.

Scheme 1. Rh(III)-Catalyzed C−H Olefination toward Isoindolinones

Figure 1. Representative biologically active molecules including isoindolinone.

catalyzed oxidative-coupling reactions between benzamides and olefins, followed by intramolecular Michael reactions to form γlactam. On the basis of the competitive reaction, it was concluded that transformation is favored for benzamides with electron-poor N-phenyl groups. Thus, Sun and Yu9 later reported an elegant improved synthesis and showed that the

Pagoclone is an anxiolytic drug from the cyclopyrrolone family that is known to bind to the benzodiazepine receptor site of the GABA-A receptor.2 In addition, pazinaclone and JM-1232 also have been reported to be benzodiazepine receptor agonists for the treatment of anxiety.3 The last two compounds have been studied as an NHE1 inhibitor and a potential drug for the treatment of cardiac arrhythmias, respectively.4 In the past decade, explosive progress has been made in the development of Cp*Rh-catalyzed C−H activation that offers © XXXX American Chemical Society

Received: December 18, 2018

A

DOI: 10.1021/acs.orglett.8b04026 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters use of an N-pentafluorophenyl benzamide directing group is crucial for this transformation. On the other hand, multicomponent reactions (MCRs), defined as the processes that combine at least three reactants in the same pot to generate a product containing most of the atoms of the starting materials,10 have been heavily exploited to prepare small molecules with atom/step economy, efficiency, and structural diversity. Therefore, the development of MCRs for the construction of biologically interesting molecules always exhibits opportunities and challenges due to the simple experimental procedures and one-pot ecofriendly synthesis method. In light of our ongoing interest in heterocycles synthesis,11 herein we designed the one-pot multicomponent isoindolinone synthesis enabled by relay catalysis of rhodium(III), starting from commercially available aldehydes, 2pyridinamine, and olefins (Scheme 1B). However, to achieve the expected reaction, the following two challenges must be overcome: (1) amide rather than iminium should be generated in situ from benzaldehydes and aromatic amine and (2) the catalytic amount of [Cp*RhCl2]2 must act as the relay catalyst for both oxidative amidation and olefination. To our delight, we overcame these challenges and obtained the target product. Unlike the many previously reported studies where the formed iminium acted as the directing group,12 we selectively realized amidation in our catalytic system, similar to that previously reported for copper and other metal catalysts.13 We began our investigation with the coupling among benzaldehyde 1a, pyridin-2-amine 2a, and ethyl acrylate 3a. Selected results are shown in Table 1. The use of [Cp*RhCl2]2

nitrogen atmosphere facilitated this one-pot transformation, improving the yield to 91% yield (entry 9). With the optimized reaction conditions in hand (Table 1, entry 9), we first investigated the scope of the substituted benzaldehydes (Scheme 2). Various benzaldehydes with Scheme 2. Scope of Benzaldehyde Substratea

Table 1. Optimization of the Reaction Conditionsa

entry

additive

solvent

yield (%)b

1 2 3 4 5 6 7 8c 9d 10e

Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 AgOAc Mn(OAc)3 CuSO4 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2

MeCN THF MeOH TFIP MeCN MeCN MeCN MeCN MeCN MeCN

70 10 trace trace trace trace trace 40 91 76

a

Isolated yields are given. Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), 3a (0.4 mmol), [RhCp*Cl2]2 (2.5 mol %), Cu(OAc)2 (0.4 mmol), MeCN (2 mL), under N2 atmosphere, 80 °C, 8 h. PMP = para-methoxyphenyl.

a

Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), 3a (0.4 mmol), [RhCp*Cl2]2 (2.5 mol %), additive (0.4 mmol), solvent (2 mL), 80 °C, 8 h. bYields of isolated products. cReaction at 60 °C. dUnder N2 atmosphere. eCu(OAc)2 2.0 equiv. TFIP = hexafluoroisopropanol.

valuable functional groups such as methoxy, methylthio, bromo, cyano, ester, and acyl reacted smoothly with 2a and 3a to afford the corresponding isoindolinones (4b−4i) in moderate to excellent yields (45−95%), thus offering a broad range of opportunities for further derivation. In addition, the structure of 4h was further confirmed by single-crystal X-ray analysis. These results show that the reactions of the benzaldehydes bearing electron-donating and -withdrawing groups at the para position had no obvious effect on this transformation. Additionally, when meta-substituted benzaldehydes were applied, good regioselectivity favoring the activation of the less hindered C−H bond was observed, and the sole product was obtained in good yields (4j and 4k). However, for the ortho- and polysubstituted benzaldehydes, the yields of the desired products were lower (4l−4o). Heteroaryl and naphthyl substituents were also compatible, and the expected products were found in moderate

as the single catalyst and Cu(OAc)2 as the oxidant in MeCN yielded lactam 4a in 70% yield (Table 1, entry 1). Encouraged by this preliminary observation, we attempted to improve the reaction efficiency by screening various solvents and oxidant (entries 2−7). It was found that Cu(OAc)2 was the best oxidant. Among the screened solvents, MeCN afforded the best yield. Lowering of the temperature to 60 °C resulted in a lower yield (entry 8). An attempt to lower the loading of Cu(OAc)2 also failed, because a smaller yield was obtained (entry 10). On the other hand, it was found that conducting the reaction under B

DOI: 10.1021/acs.orglett.8b04026 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters yields (4p and 4q). Interestingly, using 1,4-benzenedicarboxaldehyde as the substrate, the expected symmetrical product 4r was isolated. We then investigated the scope of the olefin-coupling partner in this transformation. As shown in Scheme 3, electron-deficient

Scheme 4. Synthetic Application and Diversification

Scheme 3. Scope of Olefin- and Aniline-Coupling Partnersa

good yields by reduction and hydrolysis from 4, respectively (Scheme 4d). To obtain insight into the reaction mechanism proposed in Scheme 5B, several control experiments were performed. First, Scheme 5. Proposed Mechanism

a

Isolated yields are given. Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), 3 (0.4 mmol), [RhCp*Cl2]2 (2.5 mol %), Cu(OAc)2 (0.4 mmol), MeCN (2 mL), under N2 atmosphere, 80 °C, 8 h.

olefins including acrylate, ethyl vinyl ketone, acrylonitrile, and acrylamide can be coupled in good yield to provide lactam products (5a−5g). Meanwhile, different types of substituents at different positions on the aniline had distinct impacts on the reaction (5h−5k). It should be noted that analogues of the anxiolytic drugs pagoclone and pazinaclone can be directly prepared by this method (5l and 5m). We also tested the reaction using an electron-deficient aniline (2f, see SI) instead of a pyridine-2-amine, but it is not effective. Clearly, this strategy opens a new avenue to the synthesis of these biologically interesting scaffolds with readily available starting materials. We were particularly interested in applying this strategy to drug synthesis and accessing other compounds with naturalproduct-like cores. 6 (Pagoclone) and 8 (pazinaclone) can be directly prepared in a single step from benzaldehyde 1a, albeit with low yields (Scheme 4a,b). We were able to obtain 8 (pazinaclone) with good yield under the standard reactions using amide 7 as the starting material (Scheme 4c), suggesting that formation of amide 7 may not proceed well in this catalytic system. Furthermore, compounds 9 and 10 were obtained in

reaction among benzaldehyde 1b, pyridin-2-amine 2a, and ethyl acrylate 3a with 2 equiv of Cu(OAc)2 gave no amide 11 and product 4b (Scheme 5A, eq (1)). Second, the reaction of amide 11 with olefin 3a at the standard conditions was evaluated, showing that the expected product 4b could be isolated in 90% yield (Scheme 5A, eq (2)). We can also get evidence suggesting that the pyridine moiety plays an important role in the direction group (see SI). Next, considering that this Rh(III)-catalyzed C

DOI: 10.1021/acs.orglett.8b04026 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

Hardcastle, I. R.; Noble, M. E.; McDonnell, J. M. J. Am. Chem. Soc. 2008, 130, 16038. (c) Belliotti, T. R.; Brink, W. A.; Kesten, S. R.; Rubin, J. R.; Wustrow, D. J.; Zoski, K. T.; Whetzel, S. Z.; Corbin, A. E.; Pugsley, T. A.; Heffner, T. G.; Wise, L. D. Bioorg. Med. Chem. Lett. 1998, 8, 1499. (d) Lawson, E. C.; Luci, D. K.; Ghosh, S.; Kinney, W. A.; Reynolds, C. H.; Qi, J.; Smith, C. E.; Wang, Y.; Minor, L. K.; Haertlein, B. J.; Parry, T. J.; Damiano, B. P.; Maryanoff, B. E. J. Med. Chem. 2009, 52, 7432. (2) (a) Evans, S. M.; Foltin, R. W.; Levin, F. R.; Fischman, M. W. Behav. Pharmacol. 1995, 6, 176. (b) Sorbera, L. A.; Leeson, P. A.; Silvestre, J.; Castaner, J. Drugs Future 2001, 26, 651. (c) Stuk, T. L.; Assink, B. K.; Bates, R. C.; Erdman, D. T., Jr.; Fedij, V.; Jennings, S. M.; Lassig, J. A.; Smith, R. J.; Smith, T. L. Org. Process Res. Dev. 2003, 7, 851. (3) (a) Maguire, G.; Franklin, D.; Vatakis, N. G.; Morgenshtern, E.; Denko, T.; Yaruss, J. S.; Spotts, C.; Davis, L.; Davis, A.; Fox, P.; Soni, P.; Blomgren, M.; Silverman, A.; Riley, G. J. Clin. Psychopharmacol. 2010, 30, 48. (b) Kanamitsu, N.; Osaki, T.; Itsuji, Y.; Yoshimura, M.; Tsujimoto, H.; Soga, M. Chem. Pharm. Bull. 2007, 55, 1682. (4) (a) Schubert, G.; Rieke-Zapp, J.; Keil, J.; Kleemann, H.-W.; Hanna, R.; Huang, B.-G.; Wu, X.-D.; Gouraud, Y. Process for preparing (3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetylguanidine derivatives. U.S. Patent US20050124681, 2005; Chem Abstr. 2005, 143, 43771. (b) Bjoere, A.; Boström, J.; Davidsson, O.; Emtenäs, H.; Gran, U.; Iliefski, T.; Kajanus, J.; Olsson, R.; Sandberg, L.; Strandlund, G.; Sundell, J.; Yuan, Z.-Q. Isoindoline derivatives for the treatment of arrhythmias. WO2008008022A1, 2008. (5) (a) Wang, H.; Glorius, F. Angew. Chem., Int. Ed. 2012, 51, 7318. (b) Karthikeyan, J.; Haridharan, R.; Cheng, C. H. Angew. Chem., Int. Ed. 2012, 51, 12343. (c) Xu, X.; Liu, Y.; Park, C. M. Angew. Chem., Int. Ed. 2012, 51, 9372. (d) Fukui, Y.; Liu, P.; Liu, Q.; He, Z. T.; Wu, N. Y.; Tian, P.; Lin, G. Q. J. Am. Chem. Soc. 2014, 136, 15607. (e) Zhang, S.-S.; Wu, J.-Q.; Liu, X.; Wang, H. ACS Catal. 2015, 5, 210. (f) Guimond, N.; Fagnou, K. J. Am. Chem. Soc. 2009, 131, 12050. (g) Pham, M. V.; Ye, B.; Cramer, N. Angew. Chem., Int. Ed. 2012, 51, 10610. (h) Zhu, C.; Falck, J. R. Chem. Commun. 2012, 48, 1674. (i) Hyster, T. K.; Ruhl, K. E.; Rovis, T. J. Am. Chem. Soc. 2013, 135, 5364. (6) (a) Hyster, T. K.; Rovis, T. Chem. Commun. 2011, 47, 11846. (b) Too, P.; Wang, Y.; Chiba, S. Org. Lett. 2010, 12, 5688. (7) (a) Rakshit, S.; Patureau, F. W.; Glorius, F. J. Am. Chem. Soc. 2010, 132, 9585. (b) Morimoto, K.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2011, 76, 9548. (c) Rakshit, S.; Grohmann, C.; Besset, T.; Glorius, F. J. Am. Chem. Soc. 2011, 133, 2350. (d) Tan, X.; Liu, B.; Li, X.; Li, B.; Xu, S.; Song, H.; Wang, B. J. Am. Chem. Soc. 2012, 134, 16163. (e) Duan, P.; Lan, X.; Chen, Y.; Qian, S.-S.; Li, J. J.; Lu, L.; Lu, Y.; Chen, B.; Hong, M.; Zhao, J. Chem. Commun. 2014, 50, 12135. (f) Seoane, A.; Casanova, N.; Quiñones, N.; Mascareñas, J. L.; Gulías, M. J. Am. Chem. Soc. 2014, 136, 834. (g) Kuhl, N.; Schröder, N.; Glorius, F. Adv. Synth. Catal. 2014, 356, 1443. (h) Kim, D. S.; Seo, Y. S.; Jun, C. H. Org. Lett. 2015, 17, 3842. (i) Dateer, R. B.; Chang, S. J. Am. Chem. Soc. 2015, 137, 4908. (j) Liu, X.; Li, X.; Liu, H.; Guo, Q.; Lan, J.; Wang, R.; You, J. Org. Lett. 2015, 17, 2936. (k) Wang, X.; Tang, H.; Feng, H.; Li, Y.; Yang, Y.; Zhou, B. J. Org. Chem. 2015, 80, 6238. (l) Wu, S.-Z.; Zeng, R.; Fu, C.; Yu, Y.; Zhang, X.; Ma, S.-M. Chem. Sci. 2015, 6, 2275. (8) Wang, F.; Song, G.-Y.; Li, X.-W. Org. Lett. 2010, 12, 5430. (9) Lu, Y.; Wang, H.-W.; Spangler, J. E.; Chen, K.; Cui, P.; Zhao, Y.; Sun, W.-Y.; Yu, J.-Q. Chem. Sci. 2015, 6, 1923. (10) (a) Brauch, S.; Van Berkel, S. S.; Westermann, B. Chem. Soc. Rev. 2013, 42, 4948. (b) Cioc, R. C.; Ruijter, E.; Orru, R. V. A. Green Chem. 2014, 16, 2958. (11) (a) Zhang, Y.; Wu, Q.; Cui, S. Chem. Sci. 2014, 5, 297. (b) Zhang, Y.; Zheng, J.; Cui, S. J. Org. Chem. 2014, 79, 6490. (c) Zhang, Y.; Wang, D.; Cui, S. Org. Lett. 2015, 17, 2494. (12) (a) Jayakumar, J.; Parthasarathy, K.; Cheng, C.-H. Angew. Chem., Int. Ed. 2012, 51, 197. (b) Kadam, V. D.; Feng, B.; Chen, X.; Liang, W.; Zhou, F.; Liu, Y.; Gao, G.; You, J. Org. Lett. 2018, 20, 7071. (13) (a) Yoo, W.; Li, C. J. Am. Chem. Soc. 2006, 128, 13064. (b) Yang, S.; Yan, H.; Ren, X.; Shi, X.; Li, J.; Wang, Y.; Huang, G. Tetrahedron 2013, 69, 6431. (c) Chan, J.; Baucom, K. D.; Murry, J. A. J. Am. Chem. Soc. 2007, 129, 14106.

cascade synthesis includes a C−H activation step, a kinetic isotope effect (KIE) study was conducted (Scheme 5A, eq (3)). A primary KIE (1.9) was obtained, suggesting that C−H bond cleavage occurs during the rate-determining step.14 On the basis of these experiments and precedents reported in the literature,15 a plausible mechanism for this multicomponent synthesis was proposed (Scheme 5B). Catalytic amination between aldehydes 1a and amine 2a produces the amide intermediate A in the presence of the Rh(III) catalyst. A serves as the reagent in the next reaction step, forming rhodacycle B via a concerted metalation/deprotonation (CMD) pathway.16 Then, coordination to the olefin-coupling partner and 1,2migratory insertion provide the uncyclized intermediate C. Reoxidation of the Rh(I) to Rh(III) by Cu(OAc)2 completes the catalytic cycle. C subsequently undergoes an in situ Michael addition to give γ-lactam products 4 or 5. In summary, we have successfully developed a highly efficient Rh(III) relay catalysis protocol for the synthesis of isoindolinone from simple starting materials in a single operation. Antianxiety and anticonvulsant drugs pagoclone and pazinaclone can be prepared in one step, showing the usefulness of this novel, onepot, three-component reaction. Furthermore, this convenient methodology demonstrates that N-pyridin-2-yl benzamide can act as an effective directing group, which may find broader application in Rh(III) catalysis.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b04026. Detailed experimental procedures and characterization data for new compounds 4 and 5 (PDF) Accession Codes

CCDC 1835723 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (Y.Z.) *E-mail: [email protected] (G.Z.) ORCID

Yan Zhang: 0000-0002-0694-5131 Gangguo Zhu: 0000-0003-4384-824X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for financial support from the NSFC (21702188, 21672191) and the Natural Science Foundation of Zhejiang Province (LQ17B020001).

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REFERENCES

(1) (a) Wrobel, J.; Dietrich, A.; Woolson, S. A.; Millen, J.; McCaleb, M.; Harrison, M. C.; Hohman, T. C.; Sredy, J.; Sullivan, D. J. Med. Chem. 1992, 35, 4613. (b) Riedinger, C.; Endicott, J. A.; Kemp, S. J.; Smyth, L. A.; Watson, A.; Valeur, E.; Golding, B. T.; Griffin, R. J.; D

DOI: 10.1021/acs.orglett.8b04026 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters (14) Simmons, E. M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51, 3066. (15) For reviews on Rh(III)-catalyzed C−H functionalization, see: (a) Satoh, T.; Ueura, K.; Miura, M. Pure Appl. Chem. 2008, 80, 1127. (b) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624. (c) Song, G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651. (16) (a) Davies, D. L.; Al-Duaij, O.; Fawcett, J.; Giardiello, M.; Hilton, S. T.; Russell, D. R. Dalton Trans 2003, 21, 4132. (b) Carr, K. J. T.; Davies, D. L.; Macgregor, S. A.; Singh, K.; Villa-Marcos, B. Chem. Sci. 2014, 5, 2340.

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DOI: 10.1021/acs.orglett.8b04026 Org. Lett. XXXX, XXX, XXX−XXX